Data mining flags 4 potentially risky drug pairs

"Columbia data scientists, in collaboration with the Tribune, identified drug pairs associated with an increased risk of QT prolongation, a heart condition that can lead to a potentially fatal arrhythmia. The results are based on records from a publicly available FDA database as well as patient archives at NewYork-Presbyterian/Columbia University Medical Center. The Columbia researchers stress the results are preliminary and do not demonstrate cause and effect. Further studies and, potentially, a clinical trial are needed. In a published paper on the results, the scientists cite eight drug combinations. The team agreed that four (below) were worthy of further study via cellular testing.

The Tribune contacted firms that originally developed the drugs or are current sales leaders. They emphasized their commitment to safety. Citing medical literature or their own research, several companies said they had seen no evidence that their drugs caused such interactions."

Metoprolol

Fosphenytoin

FOR MEN:

In milliseconds

Percentage of patients with a QT interval of more than 500 milliseconds**

Patients taking one drug

13%

Patients taking both drugs

22%

Change in patients with long QT interval

Percentage-point difference

+9

Drugmaker response:

Novartis, which said it created and still manufactures metoprolol, did not address questions about the findings. “Systemic safety risk assessment is performed for all Novartis compounds on an annual basis,” the company said in a written statement. "Novartis is committed to continue following industry practice of assessing the risk of its drugs to prolong the QT interval and to share collected data with health authorities throughout the world on an ongoing basis." According to IMS Health data, the 2014 sales leader for metoprolol was AstraZeneca, which declined to comment on the study. "We can confirm," the company said, "that AstraZeneca performed testing for QT prolongation during drug development as defined by the regulatory requirements and our safety databases showed no signal of QT prolongation attributed to metoprolol alone or concomitantly" with fosphenytoin. Pfizer, the 2014 sales leader for fosphenytoin, said it was unaware of any data for the drug that signals concerns regarding QT intervals. "Ensuring the safety of patients and the appropriate use of our medicines is of paramount concern to Pfizer," the company said. "It is for this reason that we continually monitor the safety and efficacy of our products to ensure the benefit and risks are accurately described in our label. We work closely with FDA and regulatory bodies across the globe, to ensure that all product labels include the most up to date medical information."

Percentage of patients with a QT interval of more than 500 milliseconds**

Patients taking one drug

Patients taking both drugs

Change in patients with long QT interval

Percentage-point difference

FOR WOMEN:

In milliseconds

Percentage of patients with a QT interval of more than 500 milliseconds**

Patients taking one drug

13%

Patients taking both drugs

25%

Change in patients with long QT interval

Percentage-point difference

+12

Drugmaker response:

According to IMS Health data, the 2014 sales revenue leader for cefazolin was B. Braun, which declined to comment. Sanofi, which received FDA approval for Demerol (meperidine hydrochloride) in 1942, said it would assess the findings. "Sanofi is not aware of any evidence, including in medical literature, about a potential drug-drug interaction between meperidine and cefazolin," the company said. IMS Health data show the 2014 sales leader for meperidine was Hospira, now part of Pfizer. Pfizer said it was unaware of any data for the drug that signals concerns regarding QT intervals. "Ensuring the safety of patients and the appropriate use of our medicines is of paramount concern to Pfizer," the company said. "It is for this reason that we continually monitor the safety and efficacy of our products to ensure the benefit and risks are accurately described in our label. We work closely with FDA and regulatory bodies across the globe, to ensure that all product labels include the most up to date medical information."

Ceftriaxone

Lansoprazole

FOR MEN:

In milliseconds

Percentage of patients with a QT interval of more than 500 milliseconds**

Patients taking one drug

14%

Patients taking both drugs

19%

Change in patients with long QT interval

Percentage-point difference

+5

Drugmaker response:

Ceftriaxone is also known by the brand name Rocephin. Roche, which discovered ceftriaxone, declined to comment on the study until the research was published in a medical journal. The company said it had no prior evidence that ceftriaxone and lansoprazole in combination affect the QT interval. Lansoprazole is also known as Prevacid. Takeda, which helped develop lansoprazole, said it would analyze the results, as it does with other research. "No concerns were identified with QT prolongation during clinical development" of lansoprazole, the company said. "Further, all ongoing signaling and allied safety activities have supported this position to date."

Meperidine

Vancomycin

FOR WOMEN:

In milliseconds

Percentage of patients with a QT interval of more than 500 milliseconds**

Patients taking one drug

20%

Patients taking both drugs

28%

Change in patients with long QT interval

Percentage-point difference

+8

Drugmaker response:

Sanofi, which received FDA approval for Demerol (meperidine hydrochloride) in 1942, said it would assess the findings. The company said it was unaware of any evidence of a potential interaction between meperidine and vancomycin. "During drug development, meperidine's impact on the ECG parameters was assessed," the company said. "We assessed these parameters in accordance with the international recommendations and regulatory requirements in effect at the time of the study." IMS Health data show the 2014 sales leader for meperidine was Hospira, now part of Pfizer. Pfizer said it was unaware of any data for the drug that signals concerns regarding QT intervals. "Ensuring the safety of patients and the appropriate use of our medicines is of paramount concern to Pfizer," the company said. "It is for this reason that we continually monitor the safety and efficacy of our products to ensure the benefit and risks are accurately described in our label. We work closely with FDA and regulatory bodies across the globe, to ensure that all product labels include the most up to date medical information." Lilly, the innovator of vancomycin, said it could not comment until it examined the study and its findings.

* Difference in average highest QTc value in 36-day period for patients prescribed both drugs vs. one drug. QTc is QT interval duration corrected for heart rate.